The present invention relates to a novel triazolopurine derivative which exhibits an adenosine A3 receptor affinity, a pharmaceutical composition containing the derivative, and an adenosine A3 receptor affinitive agent.
J. Heterocyclic Chem., 31, 1171 (1994) disclosed that 2-aryl-8-fluorobenzyl-1,2,4-triazolo[5,1-i]purine is useful as an adenosine A2 receptor antagonist.
An object of the present invention is to provide a novel compound which has an affinity to an adenosine A3 receptor.
The triazolopurine derivative of the present invention is represented by the general formula (1): 
wherein R1 represents a lower alkoxy lower alkyl group, a lower alkylsulfinyl lower alkyl group, a lower alkylsulfonyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a cycloalkyl group, a halogen-substituted lower alkyl group, a phosphono lower alkyl group, a lower alkylphosphono lower alkyl group, a di-lower alkylphosphono lower alkyl group, a lower alkanoyloxy lower alkyl group, a hydroxy lower alkyl group, a di-lower alkylamino lower alkyl group, a phenyl lower alkoxy lower alkyl group, or a lower alkylthio lower alkyl group; R2 represents a phenyl group which may have, as a substituent, 1 to 3 groups selected from the group consisting of lower alkyl group, lower alkoxy group, halogen atom, halogen-substituted lower alkyl group, and phenyl group.
The triazolopurine derivative of the present invention is a novel compound which has never been described in reference documents.
In the present invention, R1 is preferably a lower alkoxy lower alkyl group, a lower alkylthio lower alkyl group, a lower alkylsulfinyl lower alkyl group, a lower alkylsulfonyl lower alkyl group, or a carboxyl lower alkyl group.
R1 is more preferably a methoxymethyl group, an ethoxymethyl group, a 2-methoxyethyl group, a 2-methylsulfinylethyl group, a 2-methylsulfonylethyl group, a 2-carboxyethyl group, a 3-carboxypropyl group, a 4-carboxybutyl group, or a 2-methylthioethyl group.
R2 is preferably a phenyl group, a 4-biphenylyl group, a 4-n-propoxyphenyl group, a 4-t-butylphenyl group, a 4-chlorophenyl group, a 4-trifluoromethylphenyl group, or a 3,4,5-trimethoxyphenyl group.
It is expected that the triazolopurine derivative of the present invention is applied to antihypertensive agent, antiallergic agent, anti-inflammatory agent, remedy for ischemic disease, remedy for leukemia, antipruritic agent, expectorants, antitussives, remedy for asthma, and analgesic, as a compound capable of binding with an adenosine A3 receptor, because of its excellent affinity to an adenosine A3 receptor.
Accordingly, the present invention also provides a pharmaceutical composition comprising the triazolopurine derivative described above and a pharmaceutically acceptable carrier.
Specifically, the present invention provides an adenosine A3 receptor affinitive agent comprising the triazolopurine derivative described above as an active ingredient.
In the present invention, the lower alkyl group includes, for example, straight-chain or branched lower alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, isopropyl, isopentyl, neopentyl, and 1-ethylpropyl.
The lower alkoxy group includes, for example, straight-chain or branched lower alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The lower alkoxy lower alkyl group includes, for example, lower alkoxy lower alkyl groups wherein both the alkoxy moiety and the alkyl moiety have 1 to 6 carbon atoms, such as methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, t-butoxymethyl, pentyloxymethyl, hexyloxymethyl, 1-methoxyethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, 2-ethoxyethyl, and 3-propoxypropyl.
The lower alkylsulfinyl lower alkyl group includes, for example, lower alkylsulfinyl lower alkyl groups wherein the alkyl moiety has 1 to 6 carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, butylsulfinylmethyl, t-butylsulfinylmethyl, pentylsulfinylmethyl, hexylsulfinylmethyl, 1-methylsulfinylethyl, 2-methylsulfinylethyl, 3-methylsulfinylpropyl, 4-methylsulfinylbutyl, 5-methylsulfinylpentyl, and 6-methylsulfinylhexyl.
The lower alkylsulfonyl lower alkyl group includes, for example, lower alkylsulfonyl lower alkyl groups wherein the alkyl moiety has 1 to 6 carbon atoms, such as methylsulfonylmethyl, ethylsulfonylmethyl, propylsulfonylmethyl, butylsulfonylmethyl, t-butylsulfonylmethyl, pentylsulfonylmethyl, hexylsulfonylmethyl, 1-methylsulfonylethyl, 2-methylsulfonylethyl, 3-methylsulfonylpropyl, 4-methylsulfonylbutyl, 5-methylsulfonylpentyl, and 6-methylsulfonylhexyl.
The lower alkoxycarbonyl lower alkyl group includes, for example, lower alkoxycarbonyl lower alkyl groups wherein both the alkoxy moiety and the alkyl moiety have 1 to 6 carbon atoms, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, butoxycarbonylmethyl, pentyloxycarbonylmethyl, hexyloxycarbonylmethyl, 1-methoxycarbonylethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4-methoxycarbonylbutyl, 5-methoxycarbonylpentyl, 6-methoxycarbonylhexyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, and 4-ethoxycarbonylbutyl.
The carboxy lower alkyl group includes, for example, carboxy lower alkyl groups wherein the alkyl moiety has 1 to 6 carbon atoms, such as carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, and 6-carboxyhexyl.
The lower alkylthio lower alkyl group includes, for examples, lower alkylthio lower alkyl groups wherein the alkyl moiety has 1 to 6 carbon atoms, such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, butylthiomethyl, t-butylthiomethyl, pentylthiomethyl, hexylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 3-methylthiopropyl, 4-methylthiobutyl, 5-methylthiopentyl, 6-methylthiohexyl, 2-ethylthioethyl, and 3-propylthiopropyl.
The halogen-substituted lower alkyl group includes, for example, perfluoro lower alkyl groups wherein the alkyl moiety has 1 to 6 carbon atoms, such as trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl, and tridecafluorohexyl.
The cycloalkyl group includes, for example, cycloalkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The phosphono lower alkyl group includes, for example, phosphono lower alkyl groups wherein the alkyl moiety has 1 to 6 carbon atoms, such as phosphonomethyl, 1-phosphonoethyl, 2-phosphonoethyl, 3-phosphonopropyl, 4-phosphonobutyl, 5-phosphonopentyl, and 6-phosphonohexyl.
The lower alkylphosphono lower alkyl group includes, for example, lower alkylphosphono lower alkyl groups wherein the alkyl moiety has 1 to 6 carbon atoms, such as methylphosphonomethyl, ethylphosphonomethyl, propylphosphonomethyl, butylphosphonomethyl, pentylphosphonomethyl, hexylphosphonomethyl, 2-ethylphosphonoethyl, 1-ethylphosphonoethyl, 3-ethylphosphonopropyl, 4-ethylphosphonobutyl, 5-ethylphosphonopentyl, and 6-ethylphosphonohexyl.
The di-lower alkylphosphono lower alkyl group includes, for example, di-lower alkylphosphono lower alkyl groups wherein the alkyl moiety has 1 to 6 carbon atoms, such as dimethylphosphonomethyl, diethylphosphonomethyl, dipropylphosphonomethyl, dibutylphosphonomethyl, dipentylphosphonomethyl, dihexylphosphonomethyl, ethylmethylphosphonomethyl, 2-diethylphosphonoethyl, 1-diethylphosphonoethyl, 3-diethylphosphonopropyl, 4-diethylphosphonobutyl, 5-diethylphosphonopentyl, and 6-diethylphosphonohexyl.
The lower alkanoyloxy lower alkyl group includes, for example, lower alkanoyloxy lower alkyl groups wherein both the alkanoyl moiety and the alkyl moiety have 1 to 6 carbon atoms, such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, hexanoyloxymethyl, heptanoyloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 3-acetoxypropyl, 4-acetoxybutyl, 5-acetoxypentyl, and 6-acetoxyhexyl.
The hydroxy lower alkyl group includes, for example, hydroxy lower alkyl groups wherein the alkyl moiety has 1 to 6 carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, and 6-hydroxyhexyl.
The di-lower alkylamino lower alkyl group includes, for example, di-lower alkylamino lower alkyl groups wherein the alkyl moiety has 1 to 6 carbon atoms, such as dimethylaminomethyl, diethylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, dipentylaminomethyl, dihexylaminomethyl, ethylmethylaminomethyl, 2-dimethylaminoethyl, 1-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, and 6-dimethylaminohexyl.
The phenyl lower alkoxy lower alkyl group includes, for example, phenyl lower alkoxy lower alkyl groups wherein both the alkoxy moiety and the alkyl moiety have 1 to 6 carbon atoms, such as benzyloxymethyl, 2-phenylethoxymethyl, 3-phenylpropoxymethyl, 4-phenylbutoxymethyl, 5phenylpentyloxymethyl, 6-phenylhexyloxymethyl, 1-benzyloxyethyl, 2-benzyloxyethyl, 3-benzyloxypropyl, 4-benzyloxybutyl, 5-benzyloxypentyl, and 6-benzyloxyhexyl.
The phenyl group which optionally has a group selected from lower alkyl group, lower alkoxy group, halogen atom, halogen-substituted lower alkyl group, and phenyl group as a substituent includes, for example, phenyl groups which optionally have 1 to 3 substituents, such as 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-t-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4-diethylphenyl, 3,4-dipropylphenyl, 3,4-dibutylphenyl, 3,4-dipentylphenyl, 3,4-dihexylphenyl, 3,4,5-trimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,6-trimethylphenyl, 2,4,5-trimethylphenyl, 3,4,5-triethylphenyl, 3,4,5-tripropylphenyl, 3,4,5-tributylphenyl, 3,4,5-tripentylphenyl, 3,4,5-trihexylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,4-dipropoxyphenyl, 3,4-dibutoxyphenyl, 3,4-dipentyloxyphenyl, 3,4-dihexyloxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 3,4,5-triethoxyphenyl, 3,4,5-tripropoxyphenyl, 3,4,5-tributoxyphenyl, 3,4,5-tripentyloxyphenyl, 3,4,5-trihexyloxyphenyl, 4-methoxy-3-methylphenyl, 4-methoxy-2-methylphenyl, 3-methoxy-2-methylphenyl, 4-methoxy-3,5-dimethylphenyl, 4-biphenylyl, 3-biphenylyl, 2-biphenylyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-heptafluoropropylphenyl, 4-nonafluorobutylphenyl, 4-undecafluoropentylphenyl, 4-tridecafluorohexylphenyl, 2,4-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 2,4,6-tris(trifluoromethyl)phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl group, in addition to phenyl group. All of the lower alkyl group, the lower alkoxy group, and the halogen-substituted lower alkyl group are groups having 1 to 6 carbon atoms.
The compound (1) of the present invention can be prepared by the reaction scheme-1 to reaction scheme-6. 
wherein R1A represents a lower alkoxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a cycloalkyl group, a halogen-substituted lower alkyl group, a di-lower alkylphosphono lower alkyl group, a lower alkanoyloxy lower alkyl group, a di-lower alkylamino lower alkyl group, a phenyl lower alkoxy lower alkyl group, or a lower alkylthio lower alkyl group; R2 is as defined above; and Y and Z are the same or different and represent a lower alkyl group.
First, a compound represented by the formula (2) is reacted with an orthoester derivative represented by the formula (3) to obtain an imino ester derivative represented by the formula (4). This reaction is carried out by adding the orthoester derivative (3) in an equimolar amount or more relative to the amount of the compound (2) and heating at a temperature within a range from 50xc2x0 C. to reflux temperature for about 10 minutes to 5 hours in the absence of a solvent, or in an inert solvent. As the inert solvent, for example, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), methanol, diphenyl ether, xylene, and diethylene glycol dimethyl ether can be used.
The resulting imino ester derivative (4) is reacted with an acyl hydrazine derivative represented by the formula (5), after the ester derivative is purified according to a conventional method or not, to obtain the compound (6). This reaction is carried out by adding the acyl hydrazine derivative (5) in an equimolar amount or slightly more relative to the amount of the imino ester derivative (4) in an inert solvent, optionally adding a catalytic amount of 1,8-diazabicyclo[5,4,0]-7-undecene and heating at a temperature within a range from 50xc2x0 C. to reflux temperature for about 1 to 50 hours. The inert solvent includes the same solvents as those described above. If necessary, the reaction solution may be alkalified by adding an aqueous sodium hydroxide solution and an aqueous potassium hydroxide solution and reacted furthermore at a temperature within a range from 0xc2x0 C. to room temperature for about 10 minutes to 50 hours after the completion of the heating reaction.
Then, the compound (6) is converted into an amine compound (7) by refluxing in an aqueous solution of mineral acid such as hydrochloric acid or sulfuric acid for 5 minutes to 50 hours.
Then, the amine compound (7) is acylated. This acylation can be carried out by reacting the amine compound (7) with a carboxylic acid chloride (8) in an amine-based inert solvent such as pyridine, lutidine, triethylamine, or 4-(N,N-dimethylamino)pyridine. In this reaction, the carboxylic acid chloride (8) is used in an equimolar amount or more and the reaction is completed within about 10 minutes to 3 hours at a temperature within a range from 0xc2x0 C. to reflux temperature. Since a compound substituted with a plurality of acyl groups may be included sometime in the acylation reaction, the inclusion can optionally be converted into the objective monoacyl compound (9) by refluxing the product, together with a catalytic amount of an alkaline such as anhydrous potassium carbonate or anhydrous sodium carbonate, in an inert solvent such as methanol or ethanol for about 10 minutes to 2 hours.
Subsequently, the monoacyl compound (9) thus obtained is converted into a compound (1A) of the present invention by the cyclization reaction. The cyclization reaction is carried out by reacting the monoacyl compound (9) with a halogenated trialkylsilane in an inert solvent in the presence of a base.
As the inert solvent, for example, aromatic and aliphatic hydrocarbons such as benzene, toluene, xylene, and petroleum ether; ethers such as diethyl ether and tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; and aliphatic nitriles such as acetonitrile can be used. As the base, for example, tertiary amine such as triethylamine, diisopropylethylamine, N,N-diethylaniline, N-methyl morpholine, pyridine, or 4-(N,N-dimethylamino)pyridine can be preferably used. As the halogenated trialkylsilane, for example, chlorotrialkylsilane such as chlorotrimethylsilane, chlorotriethylsilane, chloroethyldimethylsilane, chlorodimethylpropylsilane, chlorobutyldimethylsilane, chlorotripropylsilane, tributylchlorosilane, or chloroethylmethylpropylsilane can be preferably used.
The amount of the halogenated trialkylsilane and base to be used is not specifically limited, but is generally controlled to an equal equivalent weight or more, and preferably from 3- to 20-fold equivalent weight relative to the amount of the monoacyl compound (9). The cyclization reaction is usually completed within about 0.5 to 100 hours at a temperature within a range from 0 to 100xc2x0 C. 
wherein R1B represents a lower alkoxycarbonyl lower alkyl group; R1C represents a carboxy lower alkyl group; and R2 is as defined above.
As shown in the reaction scheme-2, a compound (1B) of the present invention is converted into a compound (1C) of the present invention by the hydrolysis reaction. The reaction is carried out by treating with an alkali such as aqueous sodium hydroxide solution or aqueous potassium hydroxide solution, in an inert solvent such as methanol or ethanol. The amount of the alkali to be used is preferably controlled to an equal equivalent weight or more relative to the amount of the compound (1B). The reaction is completed within about 0.5 to 10 hours at a temperature within a range from 0xc2x0 C. to about room temperature. 
wherein R1D represents a lower alkylthio lower alkyl group; R1E represents a lower alkylsulfinyl lower alkyl group or a lower alkylsulfonyl lower alkyl group; and R2 is as defined above.
As shown in the reaction scheme-3, a compound (1D) of the present invention is converted into a compound (1E) of the present invention by the oxidization reaction. The oxidization reaction is carried out by using hydrogen peroxide as an oxidizing agent in acetic acid, or using m-chloroperbenzoic acid or sodium periodate as an oxidizing agent in an inert solvent such as dichloromethane or carbon tetrachloride. In case the oxidization reaction is carried out until the sulfinyl compound is obtained, the amount of the oxidizing agent to be used is controlled to an equal equivalent weight or slightly more relative to the raw compound and the reaction is carried out at a temperature within a range from 0xc2x0 C. to about room temperature for about 15 minutes to 10 hours. In case the oxidization reaction is carried out until the sulfonyl compound is obtained, the amount of the oxidizing agent to be used is controlled to a 2-fold equivalent weight or more relative to the raw compound and, if necessary, a catalyst such as sodium tungstate is added and, moreover, the reaction is carried out at a temperature within a range from 0xc2x0 C. to about reflux temperature for about 15 minutes to 10 hours.
The sulfonyl compound can also be obtained by subjecting the resulting sulfinyl compound to the oxidation reaction again. The conditions to be employed may be either of two conditions described above. 
wherein R1F represents a di-lower alkylphosphono lower alkyl group; R1G represents a lower alkylphosphono lower alkyl group; and R2 is as defined above.
According to the reaction scheme-4, the objective compound (1G) can be obtained by reacting a compound (1F) with a halogenated lithium such as lithium chloride, lithium bromide or lithium iodide and treating the resulting compound with an aqueous solution of mineral acid such as hydrochloric acid or sulfuric acid at a stage of post-treatment. The reaction is carried out by using an excess amount of the halogenated lithium in an inert solvent such as acetonitrile or DMF at a temperature within a range from room temperature to reflux temperature of the solvent for 5 to 24 hours. 
wherein R1H represents a phosphono lower alkyl group; and R1F and R2 are as defined above.
According to the reaction scheme-5, the objective compound (1H) can be obtained by reacting a compound (1F) with a halogenated trialkylsilane such as chlorotrimethylsilane or chlorotriethylsilane and treating the resulting compound with an aqueous solution of mineral acid such as hydrochloric acid or sulfuric acid at a stage of post-treatment. The reaction is carried out in an inert solvent such as acetonitrile or propionitrile in the presence of an alkaline metal iodide salt such as sodium iodide or potassium iodide. The amount of the halogenated trialkylsilane and alkaline metal iodide salt to be used is controlled to a 2-fold equivalent weight or more relative to the compound (1F) and the reaction is completed within about 2 to 12 hours at a temperature within a range from room temperature to reflux temperature of the solvent. 
wherein R1J represents a lower alkanoyloxy lower alkyl group; R1K represents a hydroxy lower alkyl group; and R2 is as defined above.
According to the reaction scheme-6, a compound (1J) can be converted into the objective compound (1K) by hydrolysis. The hydrolysis reaction can be carried out by employing the same conditions as those in the hydrolysis reaction of the reaction scheme-2.
The objective compound in each process of the reaction scheme can be easily isolated and purified by a conventional separation means. The separation means includes adsorption chromatography, preparative thin-layer chromatography, recrystallization, solvent extraction or the like.
Among the compounds (1) of the present invention prepared as described above, it is considered that the compound includes the following four structural formulas as a tautomer and the compounds (1) can be represented by any of the structural formulas: 
wherein R1 and R2 are as defined above.
The compounds (1) of the present invention can be formed into pharmaceutically acceptable acid addition salts, and these salts are also included in the present invention. The acid capable of forming these acid addition salts includes, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid; and organic acids such as oxalic acid, fumaric acid, maleic acid, tartaric acid, citric acid, and p-toluenesulfonic acid. The acid addition salts can be formed by a conventional method.
The compounds (1) of the present invention can be formed into alkaline metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and copper salts, and these salts can also be included in the present invention.
The compounds (1) of the present invention are used in the form of a general pharmaceutical preparation by using, together with a suitable non-toxic preparation carrier. The preparation carrier include diluents and excipients, such as fillers, extenders, binders, humectants, disintegrators, surfactants, and lubricants, which are usually used according to the form of the preparation, and these are appropriately selected and used according to the unit dosage form of the resulting preparation.
As the unit dosage form of the pharmaceutical preparation using the compound (1), various forms can be selected according to the therapeutic purposes and typical examples thereof include tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, injections (e.g. liquid preparations, suspensions, etc.), and ointments.
In case of forming into the form of tablets, there can be used, as the preparation carrier, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and potassium phosphate; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, and polyvinyl pyrrolidone; disintegrators such as sodium carboxymethylcellulose, calcium carboxymethylcellulose, low substituted hydroxypropylcellulose, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, and calcium carbonate; surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, and stearic acid monoglyceride; disintegration inhibitors such as sucrose, stearin, cacao butter, and hydrogenated oil; absorption accelerators such as quaternary ammonium base and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as purified talc, stearate, powdered boric acid, and polyethylene glycol.
If necessary, tablets can be formed into tablets coated with a common coating, for example, sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film coating tablets, double layered tablets, or mutilayer tablets.
In case of forming into the form of pills, there can be used, as the preparation carrier, excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, and talc; binders such as gum arabic, powdered tragacanth, gelatin, and ethanol; and disintegrators such as laminaran and agar.
In case of forming into the form of suppositories, there can be used, as the preparation carrier, polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, and semisynthetic glyceride.
Capsules are usually prepared by mixing the compound (1) of the present invention with various preparation carriers mentioned above and filling a hard gelatin capsule or a soft capsule with the mixture.
In case of preparing as injections such as liquid preparations, emulsions or suspension, these are preferably sterilized and are isotonic with blood. In case of forming into the form of injections, there can be used, as the diluent, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, or polyoxyethylene sorbitan fatty acid esters. In this case, salt, glucose or glycerin may be contained in an enough amount to prepare an isotonic solution and common solubilizers, buffer agents or soothing agents may also be added.
If necessary, the pharmaceutical preparation further contains colorants, preservatives, perfumes, flavors, sweeteners, or other drugs.
In case of forming into the form such as paste, cream, or gel, there can be used, as the diluent, white vaseline, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicon, and bentonite.
The amount of the compound (1) of the present invention to be incorporated in the pharmaceutical preparation is not specifically limited and appropriately selected from a wide range, but is preferably within a range from about 1 to 85% by weight based on the pharmaceutical preparation.
The administration method of the pharmaceutical preparation is not specifically limited, but is appropriately decided according to the form of preparations, age of patients, sex and other conditions, or conditions of diseases. For example, tablets, pills, liquid preparations, suspensions, emulsions, granules and capsules are orally administered, while injections are intravenously administered alone or in combination with a conventional fluid such as glucose or amino acid, or intramuscularly, intracutaneously, subcutaneously or intraperitoneally administered alone, if necessary. Furthermore, suppositories are intrarectally administered.
The dose of the pharmaceutical preparation varies depending on the administration method, age of patients, sex and other conditions, or conditions of diseases, but a dairy dose of the compound (1) of the present invention is usually within a range from about 0.5 to 20 mg/kg-weight, and preferably from about 1 to 10 mg/kg-weight. The pharmaceutical preparation can be administered 1 to 4 times per day.
It is expected that the triazolopurine derivative of the present invention is applied to antihypertensive agent, antiallergic agent, anti-inflammatory agent, remedy for ischemic disease, remedy for leukemia, antipruritic agent, expectorants, antitassives, remedy for asthma, and analgesic because of its affinity to an adenosine A3 receptor.